The invention relates to the preparation of infection-resistant materials for use within the interior of a human or animal body, and more particularly, to the provision of certain antimicrobial agents into or onto polymeric materials, natural or synthetic, such as Dacron polyester, polytetrafluoroethylene, or silicone, which are usable as prostheses, grafts, implants, sutures, etc.
Infection is one of the most common complications occurring from any injury or surgical procedure. As a specific example, reconstructive surgery for patients suffering from isthemic vascular disease is now standard practice; however, vascular grafts employed in such surgery frequently develop infections, leading to serious, and often catastrophic, complications. Even with the use of perioperative antibiotics, the incidence of infection remains at about 1% to 5%. This low figure is misleading, however, for while the rate of infection is low, the morbidity and mortality associated with such infection is quite high. The mortality rate of infected aortic implant has been reported to be as high as 100 percent. Excision of an infected prosthesis is the typical treatment. In the case of infected distal grafts, the result is frequently limb loss. The problems, and known solutions, associated with vascular prosthetic infection are set forth in detail in Infections in Surgery, pp. 45-55, September 1982.
When infection is present prior to the operation, direct placement of a synthetic implant is often contraindicated. This could result in the need for an extra-anatomic bypass procedure, or the sacrifice of a limb. Such catastrophic complications have stimulated the search for an infection-resistant vascular prosthesis which is also compatible with biological vascular tissue.
It is known that, while vascular grafts remain susceptible to bacterial infection until the complete pseudointima has formed, graft contamination usually occurs at the time of implantation. It is difficult, if not impossible, to totally eliminate bacteria during surgical proceedings. At best, the surgeon attempts to provide a bacteriostatic environment for the graft, i.e., an environment in which the concentration of bacteria is kept at a low level by creating an environment which is hostile to bacterial growth. The attempts to limit such contamination have included application of systemic antibiotics and local irrigation with antibiotic solutions. Furthermore, the grafts are typically soaked in a solution of penicillin and heparin at the operating table immediately prior to insertion in the patient. Such attempts, however, have proven not to be completely effective, probably because of the brief residence of antibacterial agents at the implantation site. Greater success could be achieved, though, if the implantation site were kept bacteriostatic for a longer period of time.
Silver and silver compounds are recognized by those involved in fields where the prevention of infection is important, as powerful and effective bactericidal and bacteriostatic agents. Silver sulfadiazine, in particular, is known to be an excellent material for combating bacterial infection. Generally, however, the treatment of infection with silver sulfadiazine and related compounds has been approached from the standpoint of topically applying bactericidal or bacteriostatic agents in an ointment to the surface of a wound. For example, U.S. Pat. Nos. 3,761,590 and 3,792,161, the disclosures of which are herein incorporated by reference and made part of this disclosure, describe the use of silver sulfadiazine (AgSD) ointment for surface wound burn therapy.
U.S. Pat. Nos. 4,049,802 and 4,292,324, discloses zinc compounds such as zinc sulfadiazine (ZnSD), again for use in surface wound therapy. Additionally, several organic acids and their metallic salts, including silver salts, have been found to be useful in ointments for surface wound therapy. See, for example, U.S. Pat. No. 4,404,197 and U.S. patent application Ser. No. 479,029, filed Mar. 25, 1983 in the names of two of the inventors hereof, the disclosures of which are also incorporated herein by reference and made part of this disclosure. Other references also provide information on covering materials which are useful in surface wound therapy. See, e.g., U.S. Pat. No. 4,287,177 disclosing a synthetic composition suitable for use as wound coverings.
The prior art references described above all pertain to surface wound therapy. Topical application of a bactericide is not practical for an in-dwelling or surgically implanted device intended to remain in the body for a significant period of time, such as a vascular graft. Parenteral administration of antibiotics is usually unsuccessful in controlling bacterial activity at a graft or implant site because the artificial graft or implant does not have a blood supply therein. Thus, the body's natural resistance to infection is low in the graft, making it prone to infection. This problem is compounded because the circulatory system cannot transport antibiotic to the site where it is most needed. Direct incorporation of an antibiotic in the graft, however, obviates the need to rely on the circulatory system for transference of the drug. Moreover, direct incorporation places a hundred fold or greater concentration of drug at the graft site than does parenteral administration.
Application of antimicrobials at the time of insertion of the device does not solve the problem since most antimicrobial agents are rapidly absorbed into the system. However, the silver salts of certain antimicrobial agents are high molecular weight polymers (See, Inorg. Chem., Vol. 15, pp. 1807-1809 (1976)) which complex with polymeric materials such as collagen, or Dacron polyester, and release silver slowly to provide antimicrobial activity for a long time. In contrast, silver applied to Dacron polyester by evaporative techniques is not inhibitory of microbial activity.
It is, therefore, an object of the invention to provide biological or synthetic materials which are compatible with body tissues, and which also prevent bacterial and microbial infection over a significant period of time.
It is further an object of the invention to provide vascular grafts, prostheses, or implants with incorporated antibacterial or antimicrobial agents, such as metal salts of sulfonamides.
It is yet a further object of the invention to provide materials for grafts, prostheses, or implants with an incorporated antibacterial or antimicrobial agent which will remain in the mateial for long-term bacteriostatic effect.
It is still a further object of the invention to provide methods of preparing synthetic vascular grafts, prostheses, or implants with incorporated antibacterial or antimicrobial agents, wherein the material comprises, inter alia, polymeric materials such as polyester, polytetrafluoroethylene, or silk.
It is yet a still further object of the invention to provide a method of treatment designed to prevent or to alleviate infections resulting from vascular surgery or implantation, comprising the employment of the polymeric materials, herein named, with antibacterial or antimicrobial agents incorporated therewith.